Gene control of tyrosine kinase TIE2 and vascular manifestations of infections.

Ligands of the endothelial-enriched tunica interna endothelial cell kinase 2 (Tie2) are markedly imbalanced in severe infections associated with vascular leakage, yet regulation of the receptor itself has been understudied in this context. Here, we show that TIE2 gene expression may constitute a novel vascular barrier control mechanism in diverse infections. Tie2 expression declined rapidly in wide-ranging models of leak-associated infections, including anthrax, influenza, malaria, and sepsis. Forced Tie2 suppression sufficed to attenuate barrier function and sensitize endothelium to permeability mediators. Rapid reduction of pulmonary Tie2 in otherwise healthy animals attenuated downstream kinase signaling to the barrier effector vascular endothelial (VE)-cadherin and induced vascular leakage. Compared with wild-type littermates, mice possessing one allele of Tie2 suffered more severe vascular leakage and higher mortality in two different sepsis models. Common genetic variants that influence TIE2 expression were then sought in the HapMap3 cohort. Remarkably, each of the three strongest predicted cis-acting SNPs in HapMap3 was also associated with the risk of acute respiratory distress syndrome (ARDS) in an intensive care unit cohort of 1,614 subjects. The haplotype associated with the highest TIE2 expression conferred a 28% reduction in the risk of ARDS independent of other major clinical variables, including disease severity. In contrast, the most common haplotype was associated with both the lowest TIE2 expression and 31% higher ARDS risk. Together, the results implicate common genetic variation at the TIE2 locus as a determinant of vascular leak-related clinical outcomes from common infections, suggesting new tools to identify individuals at unusual risk for deleterious complications of infection.

Approach to risk identification in undifferentiated mental disorders.

OBJECTIVE: To provide primary care physicians with a novel approach to risk identification and related clinical decision making in the management of undifferentiated mental disorders. SOURCES OF INFORMATION: We conducted a review of the literature in PubMed, CINAHL, PsycINFO, and Google Scholar using the search terms diagnostic uncertainty, diagnosis, risk identification, risk assessment/methods, risk, risk factors, risk management/methods, cognitive biases and psychiatry, decision making, mental disorders/diagnosis, clinical competence, evidence-based medicine, interviews as topic, psychiatry/education, psychiatry/methods, documentation/methods, forensic psychiatry/education, forensic psychiatry/methods, mental disorders/classification, mental disorders/psychology, violence/prevention and control, and violence/psychology. MAIN MESSAGE: Mental disorders are a large component of practice in primary care and often present in an undifferentiated manner, remaining so for prolonged periods. The challenging search for a diagnosis can divert attention from risk identification, as diagnosis is commonly presumed to be necessary before treatment can begin. This might inadvertently contribute to preventable adverse events. Focusing on salient aspects of the patient presentation related to risk should be prioritized. This article presents a novel approach to organizing patient information to assist risk identification and decision making in the management of patients with undifferentiated mental disorders. CONCLUSION: A structured approach can help physicians to manage the clinical uncertainty common to risk identification in patients with mental disorders and cope with the common anxiety and cognitive biases that affect priorities in risk-related decision making. By focusing on risk, functional impairments, and related symptoms using a novel framework, physicians can meet their patients' immediate needs while continuing the search for diagnostic clarity and long-term treatment.

Évaluer les risques dans le cas de troubles mentaux indifférenciés.

OBJECTIF: Proposer aux médecins de soins primaires une approche novatrice pour la détermination des risques et la prise de décisions cliniques connexes dans la prise en charge de troubles mentaux indifférenciés. SOURCES DE L'INFORMATION: Nous avons procédé à une recherche documentaire dans PubMed, CINAHL, PsycINFO et Google Scholar à l'aide des expressions de recherche suivantes, en anglais : diagnostic uncertainty, diagnosis, risk identification, risk assessment/methods, risk, risk factors, risk management/methods, cognitive biases and psychiatry, decision making, mental disorders/diagnosis, clinical competence, evidence-based medicine, interviews as topic, psychiatry/education, psychiatry/methods, documentation/methods, forensic psychiatry/education, forensic psychiatry/methods, mental disorders/classification, mental disorders/psychology, violence/prevention and control et violence/psychology. MESSAGE PRINCIPAL: Les troubles mentaux constituent une grande part de la pratique en soins primaires; ils se présentent souvent de manière indifférenciée et ce, pendant de longues périodes. La difficile quête d'un diagnostic peut détourner l'attention de la détermination des risques, parce que nous présumons souvent qu'il faut un diagnostic avant d'amorcer un traitement. Cette situation peut avoir contribué par inadvertance à des événements indésirables. Il faudrait en priorité se concentrer sur les points saillants relatifs aux risques que présente le patient. Cet article propose une approche novatrice pour organiser les renseignements sur le patient afin d'aider à la détermination des risques et à la prise de décisions relativement à la prise en charge des patients souffrant de troubles mentaux indifférenciés. CONCLUSION: Une approche structurée peut aider les médecins à gérer l'incertitude clinique fréquente dans la détermination des risques chez des patients souffrant de troubles mentaux, et à composer avec l'anxiété et les biais cognitifs courants qui influencent la prise de décisions en matière de risques. En se concentrant sur les risques, les déficiences fonctionnelles et les symptômes connexes à l'aide d'un cadre novateur, les médecins peuvent répondre aux besoins immédiats de leurs patients tout en continuant à rechercher un diagnostic précis et à établir un traitement à long terme.

Relationship between insecure attachment and physical symptom severity is mediated by sensory sensitivity.

OBJECTIVE: Various models have been used to explain somatization, including attachment theory, which describes how formative experiences influence perceptions of vulnerability and threat. Although attachment insecurity is associated with greater physical symptoms, the mechanisms by which attachment insecurity influences the experience of physical symptoms are not clear. Sensory processing sensitivity (SPS) describes a low threshold to responding to stimuli and high emotional reactivity. It is associated with both attachment insecurity and physical symptoms. The purpose of this study is to test a model in which attachment insecurity, depression, and SPS interact to influence physical symptoms. METHODS: Cross-sectional data from the online Self-Assessment Kiosk were used (N = 186). Participants were surveyed regarding attachment insecurity (ECR-M16), physical symptom severity (PHQ-15), sensory processing sensitivity (HSPS), and depression (PHQ-9). A path analysis was used to analyze the data. RESULTS: Modal participants were white (74%) single (45%) women (80%) with university education (79%). Attachment anxiety, attachment avoidance, and sensitivity were correlated with physical symptom severity. The data suggested that sensitivity mediates between attachment anxiety and physical symptoms (ßindirect  = 0.070, p = .003 and ßdirect  = -0.030, p> .05) and this relationship remains significant when controlling for depression. CONCLUSIONS: This study extends our understanding of the potential pathways that lead individuals with attachment insecurity to experience burdensome physical symptoms by supporting a mediating role for SPS.

Mental health follow-up after deliberate self-harm and risk for repeat self-harm and death.

Morbidity and mortality after deliberate self-harm (DSH) are high, so mental health care shortly after DSH is recommended. Using population-level health data we determined the association between a mental health visit and risk for repeat DSH with or without intensive care unit (ICU) admission or all-cause death. Over two years, 23,140 individuals had emergency department treatment for DSH. Within 30 days, 10.7% had a family physician mental health visit, 17.1% visited a psychiatrist, 3.6% visited both and 68.6% neither. Individuals who received mental health follow-up had more chronic and severe mental illness and higher acuity DSH. Over five years, repeat DSH occurred in 4792 (20.7%). Repeat DSH was more common in those who had a mental health visit within 30 days. Adjusting for baseline characteristics attenuated these differences. Similar results were found for DSH with ICU admission (5.0%) and death (7.6%). More frequent follow-up was not associated with better outcome. Timely access to mental health care after DSH was poor at 31%. Follow-up care had virtually no association with subsequent risk, so treatment as usual is insufficient. Post-DSH care augmented with evidence-based interventions is required.

Childhood Adversities and Physical and Mental Health Outcomes in Adults Living with HIV: Findings from the Ontario HIV Treatment Network Cohort Study.

We sought to estimate the prevalence of childhood adversity and examine its relationship with health outcomes among people living with HIV. Study participants included 1409 adults living with HIV and receiving care in Toronto, Canada. Data on childhood adversity, health behaviors, HIV outcome measures, depression, and health-related quality of life (HRQOL) were collected through face-to-face interviews and medical records. Statistical analyses included multivariable linear and logistic regression modeling. The prevalence of any childhood adversity was 71% (individual types ranged from 11% to 44%) and higher prevalence was associated with younger age, Indigenous or African/Caribbean/Black ethnicity, lower socioeconomic status, and higher rates of cigarette smoking and nonmedicinal drug use. Greater number of childhood adversities was associated with greater odds of depression and decreasing mental HRQOL. HIV care providers need to screen for childhood adversities and address childhood trauma within the context of HIV care.

Trophoblast mitochondrial function is impaired in preeclampsia and correlates negatively with the expression of soluble fms-like tyrosine kinase 1.

Preeclampsia is a common medical complication of pregnancy that is associated with significant morbidity and mortality to the mother and the baby. Extensive human epidemiological and experimental studies suggest that excess placental soluble fms-like tyrosine kinase 1, a potent anti-angiogenic factor leads to the maternal hypertension, proteinuria and other systemic complications of preeclampsia. To evaluate the mechanisms of the aberrant placental sFlt1 expression, we studied the role of mitochondrial dysfunction as one possible etiological factor. Here, using human placental samples, we demonstrate that both the activity and expression of a mitochondrial electron transport chain enzyme cytochrome C oxidase (COX) is diminished in the syncytiotrophoblast layer of the chorionic villi from preeclamptic subjects. In addition, there was an inverse correlation between mitochondrial COX enzyme activity and placental sFlt1 expression. Functional in situ enzyme chemistry with electron microscopy also confirmed impaired mitochondrial function in preeclampsia. Ultrastructural and morphometric analysis of mitochondria using electron microscopy demonstrated, that mitochondria are smaller in both the syncytiotrophoblast and cytotrophoblast layers of preeclamptic tissue. The etiology of the mitochondrial dysfunction in preeclampsia as a cause or effect of the placental anti-angiogenic state remains to be elucidated in future studies.

Angiopoietin-1 requires oxidant signaling through p47phox to promote endothelial barrier defense.

BACKGROUND: Reactive oxygen species (ROS) are largely considered to be pathogenic to normal endothelial function in disease states such as sepsis. We hypothesized that Angiopoietin-1 (Angpt-1), an endogenous agonist of the endothelial-specific receptor, Tie-2, promotes barrier defense by activating NADPH oxidase (NOX) signaling. METHODS AND FINDINGS: Using primary human microvascular endothelial cells (HMVECs), we found that Angpt-1 stimulation induces phosphorylation of p47phox and a brief oxidative burst that is lost when chemical inhibitors of NOX activity or siRNA against the NOX component p47phox were applied. As a result, there was attenuated ROS activity, disrupted junctional contacts, enhanced actin stress fiber accumulation, and induced gap formation between confluent HMVECs. All of these changes were associated with weakened barrier function. The ability of Angpt-1 to prevent identical changes induced by inflammatory permeability mediators, thrombin and lipopolysaccharides (LPS), was abrogated by p47phox knockdown. P47phox was required for Angpt-1 to activate Rac1 and inhibit mediator-induced activation of the small GTPase RhoA. Finally, Angpt-1 gene transfer prevented vascular leakage in wildtype mice exposed to systemically administered LPS, but not in p47phox knock out (p47-/-) littermates. CONCLUSIONS: These results suggest an essential role for NOX signaling in Angpt-1-mediated endothelial barrier defense against mediators of systemic inflammation. More broadly, oxidants generated for signal transduction may have a barrier-promoting role in vascular endothelium.

Development and validation of a brief screening instrument for psychosocial risk associated with genetic testing: a pan-Canadian cohort study.

OBJECTIVES: To develop a brief, reliable and valid instrument to screen psychosocial risk among those who are undergoing genetic testing for Adult-Onset Hereditary Disease (AOHD). DESIGN: A prospective two-phase cohort study. SETTING: 5 genetic testing centres for AOHD, such as cancer, Huntington's disease or haemochromatosis, in ambulatory clinics of tertiary hospitals across Canada. PARTICIPANTS: 141 individuals undergoing genetic testing were approached and consented to the instrument development phase of the study (Phase I). The Genetic Psychosocial Risk Instrument (GPRI) developed in Phase I was tested in Phase II for item refinement and validation. A separate cohort of 722 individuals consented to the study, 712 completed the baseline package and 463 completed all follow-up assessments. Most participants were female, at the mid-life stage. Individuals in advanced stages of the illness or with cognitive impairment or a language barrier were excluded. INTERVENTIONS: Phase I: GPRI items were generated from (1) a review of the literature, (2) input from genetic counsellors and (3) phase I participants. Phase II: further item refinement and validation were conducted with a second cohort of participants who completed the GPRI at baseline and were followed for psychological distress 1-month postgenetic testing results. PRIMARY AND SECONDARY OUTCOME MEASURES: GPRI, Hamilton Depression Rating Scale (HAM-D), Hamilton Anxiety Rating Scale (HAM-A), Brief Symptom Inventory (BSI) and Impact of Event Scale (IES). RESULTS: The final 20-item GPRI had a high reliability-Cronbach's α at 0.81. The construct validity was supported by high correlations between GPRI and BSI and IES. The predictive value was demonstrated by a receiver operating characteristic curve of 0.78 plotting GPRI against follow-up assessments using HAM-D and HAM-A. CONCLUSIONS: With a cut-off score of 50, GPRI identified 84% of participants who displayed distress postgenetic testing results, supporting its potential usefulness in a clinical setting.

The effects of gender on adolescent suicide in ontario, Canada.

OBJECTIVE: Identify patterns of suicide amongst male and female adolescents aged 11-18 years in Ontario. METHOD: All 370 adolescent suicides in Ontario between January 2000 and November 2006 were analyzed. Previous attempts, history of psychiatric treatment, location committed and method of suicide were assessed. Data was analyzed using 2-tailed t-tests and chi-square without Yates' correction. RESULTS: Male adolescent suicide was twice as common as female suicide. Males were more likely to use violent methods (p=0.0352) and females were more likely to have a history of a previous suicide attempt (p=0.0001). CONCLUSIONS: While most of the data agree with previous studies in adult populations, the ratio of male to female suicides was much lower in our adolescent population.

Hard to swallow: a systematic review of deliberate foreign body ingestion.

OBJECTIVE: Deliberate foreign body ingestion (DFBI) is often impulsively driven, repetitive and refractory to intervention and frequently necessitates multiple medical interventions. As such, the frustrations among health care providers are great, and the financial toll on health care is significant. Nevertheless, the literature on DFBI is sparse, and suggestions for treatment planning and management are limited. The authors sought to investigate and uncover efficacious treatments and strategies for preventing reoccurrence in DFBI. We build on earlier work by offering both broad and diagnosis-specific management strategies. METHOD: A literature review was performed addressing the presentation, management and prevention of reoccurrences of DFBI. Four cases of DFBI are presented illustrating those psychiatric diagnoses (psychosis, malingering, obsessive-compulsive disorder and borderline personality disorder) most frequently encountered in hospital practice. Both broad and specific treatment approaches are presented. RESULTS: Patients engaging in DFBI are best managed through a multidisciplinary approach, following acute medical management. Successful strategies for the prevention of reoccurrences of DFBI are inconclusive. CONCLUSION: Understanding the function of this behavior is critical in developing treatment for patients who engage in these dangerous, potentially life-threatening, self-injurious behaviors. An amalgam of medical, pharmacological and cognitive-behavioral interventions is recommended, as is additional research.

Adult attachment measures: a 25-year review.

OBJECTIVE: Over the past 25 years, attachment research has extended beyond infant-parent bonds to examine dyadic relationships in children, adolescents, and adults. Attachment has been shown to influence a wide array of biopsychosocial phenomena, including social functioning, coping, stress response, psychological well-being, health behavior, and morbidity, and has thus emerged as an important focus of psychosomatic research. This article reviews the measurement of adult attachment, highlighting instruments of relevance to-or with potential use in-psychosomatic research. METHODS: Following a literature search of articles that were related to the scales and measurement methods of attachment in adult populations, 29 instruments were examined with respect to their utility for psychosomatic researchers. RESULTS: Validity, reliability, and feasibility were tabulated on 29 instruments. Eleven of the instruments with strong psychometric properties, wide use, or use in psychosomatic research are described. These include the following: Adult Attachment Interview (George, Kaplan, and Main); Adult Attachment Projective (George and West); Adult Attachment Questionnaire (Simpson, Rholes, and Phillips); Adult Attachment Scale (and Revised Adult Attachment Scale) (Collins and Read); Attachment Style Questionnaire (Feeney); Current Relationship Interview (Crowell and Owens); Experiences in Close Relationships (Brennan, Clark, and Shaver) and Revised Experiences in Close Relationships (Fraley, Waller, and Brennan); Parental Bonding Instrument (Parker, Tupling, and Brown); Reciprocal Attachment Questionnaire (West and Sheldon-Keller); Relationship Questionnaire (Bartholomew and Horowitz); and Relationship Scales Questionnaire (Grifiin and Bartholomew). CONCLUSION: In addition to reliability and validity, investigators need to consider relationship focus, attachment constructs, dimensions or categories of interest, and the time required for training, administration, and scoring. Further considerations regarding attachment measurement in the context of psychosomatic research are discussed.

A novel network for mentoring family physicians on mental health issues using E-mail.

OBJECTIVE: Family practitioners are significant providers of mental health care and routinely report difficulty acquiring timely support in this area. The Collaborative Mental Health Care Network assembled groups of family practitioners and provided them with mental health practitioner mentors. This article addresses communication in the Network, its effect on family practitioners, and the role e-mail plays. METHODS: This descriptive study utilizes two sources of data: a quality assurance survey administered to family practitioners in the Network and a sampling of e-mail correspondence between family practitioners and mental health and addiction mentors, examined qualitatively. RESULTS: Family practitioners in the Network requested consultation on pharmacotherapy (53%), psychotherapy (34%), treatment review (27%), and diagnosis (24%). Satisfaction with the Network was high, with 88% of family practitioners reporting an improvement in ability to provide mental health care. E-mail analysis suggests that mentors convey information directly and indirectly and that a knowledge hierarchy, but not a power hierarchy, develops. The trusted relationship between the mentee and mentor is an important context for effective education. CONCLUSION: This model of mentoring is highly satisfactory to family practitioners and correlates with increased confidence in caring for patients with mental health issues. E-mail is a promising strategy for effective feedback and support between family practitioners and specialists.

Responsiveness to change [corrected] due to supportive-expressive group therapy, improvement in mood and disease progression in women with metastatic breast cancer.

OBJECTIVE: To compare the responsiveness of six questionnaires using three hypotheses of change: (i) change due to supportive-expressive group therapy (SEGT), (ii) improved mood defined as a small effect size (.2) on Profile of Mood States (POMS) Total Mood Disturbance score and (iii) progression of disease. METHOD: Data from the "Breast Expressive-Supportive Therapy" study, a multicentre randomized controlled trial of change due to SEGT versus standard of care in women with metastatic breast cancer were used. Questionnaires studied were: POMS, Impact of Event Scale, Psychosocial Adjustment to Illness Scale (PAIS), EORTC QLQ-C30, Mental Adjustment to Cancer and a Pain visual analog scale (VAS). Responsiveness to change was evaluated using the standardized response mean. POMS was used as the standard. RESULTS: POMS was the most responsive questionnaire to change due to SEGT. Questionnaires measuring psychosocial attributes were responsive to improvement in mood. EORTC QLQ-C30, PAIS, PAIN VAS and MAC were the most responsive to disease progression. More responsive questionnaires were associated with the smallest sample size required to detect an effect. CONCLUSIONS: Responsiveness to change is context specific. The POMS was the most responsive questionnaire to psychosocial therapy.

A multicenter study of supportive-expressive group therapy for women with BRCA1/BRCA2 mutations.

BACKGROUND: Women with a BRCA1/BRCA2 mutation experience significant challenges. These include decision-making regarding surgical options and notification to offspring and family, along with a sense of isolation, which may lead to psychological and emotional distress. The current study developed, standardized, and conducted preliminary testing of a supportive-expressive group therapy intervention designed to address these challenges. METHODS: Seventy women with a BRCA1/BRCA2 mutation recruited from familial cancer risk clinics participated in 12 sessions of supportive-expressive group therapy that lasted 6 months. Before and after measures of psychosocial functioning, knowledge, and surveillance/surgery activities were completed. RESULTS: Sixty-seven women completed the intervention. Significant improvements were observed in psychosocial functioning: cancer worries (P = 0.005), anxiety (P = 0.033), and depression (P = 0.015). Knowledge level and surveillance levels were high at baseline and there were no significant changes postintervention. A significant number of women made decisions concerning prophylactic surgery (oophorectomy/mastectomy) during and after the intervention. CONCLUSIONS: The feasibility of a supportive-expressive group for BRCA1/BRCA2 mutation carriers was demonstrated. Findings from the study are consistent with an effective intervention. However, further research is required using a randomized controlled study design.